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使用细胞条码技术在3D球形模型系统中研究药物耐药性的进化动态

Gizem Damla Yalcin¹, Kubra Celikbas Yilmaz¹, Tugce Dilber¹

¹Department of Biological Sciences, Middle East Technical University, Çankaya, Ankara, Turkey.

|September 26, 2023

概括

这项研究量化了使用细胞条形码的3D球形体中药物耐药性的演变. 我们确定了先前存在的和新的抗药机制,包括基因突变和药物排泄,用于达布拉费尼布和伊利诺坦.

科学领域:

癌症研究癌症研究
进化生物学进化生物学
基因组学就是基因组学.

背景情况:

耐药性在癌症治疗中构成了重大挑战.
了解耐药性的进化动态需要高分辨率的技术.
3D球形模型为研究瘤发生和药物耐药性提供了一个临床相关的平台.

研究的目的:

使用细胞条形码建立耐药的3D球形衍生物.
量化选择诱导的克隆动态对达布拉费尼布和义诺他干的反应.
在球形模型系统中识别药物耐药性的基因组决定因素.

主要方法:

开发带有条形码的3D球体 (HT-29和HCT-116).
诱导对达布拉费尼布和氨酸的耐药性.
用于基因组分析的全外组测序.
对药物排泄表达的分析 (ABCB1和ABCG2).

主要成果:

球体体中药物耐药性是由既存在的,又由新的耐药条形码介导的,这表明了多克隆性耐药性.
全外因子测序揭示了染色体的增长和与耐药性相关的突变.
药物排放ABCB1和ABCG2的升级有助于多种药物耐药性.

结论:

这项研究首次使用细胞条形码对球体的耐药性和进化动态进行量化.
这些发现确定了关键的基因组决定因素和机制,如先前存在的克隆和排泄,是药物耐药性的基础.
开发的模型系统为未来对癌症药物耐药性的研究提供了一个强大的工具.

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